This present application relates to the process of synthesizing α,ω-Olefins from an allylic substrate by utilizing a copper catalyzed coupling reaction with a Grignard reagent. More still particularly, the present application relates to the process of synthesizing α,ω-diolefins and more particularly, to a process for obtaining symmetrical α,ω-dienes. The process involves formation of the Grignard reagents from acyclic α,ω-dihalides that would typically contain from 3 to 10 carbons which in turn react with an allylic halide or ester in the presence of a copper catalyst. The process provides improved yields, and a simpler, more routine method of obtaining α,ω-Olefins. The present application further illustrates the use of symmetrical dienes in the various commercial synthetic routes.
Conventionally, α,ω-olefins have been prepared using a variety of methods including but not limited to the following: olefin metathesis (as disclosed in U.S. Pat. No. 5,342,985); acetate pyrolysis (Neftekhimiya 1969, 9, 767-770); and the pyrolysis of cycloalkenes in the presence of water and an amine or ammonia regulator at elevated temperatures (U.S. Pat. No. 3,622,646).
Amongst the available methods, olefin metathesis is the most common methodology and is an extremely versatile reaction for diene formation that is found in the literature. However, olefin metatheses reactions often result in complex reaction mixtures (as reported in The Journal of Molecular Catalysis A: Chemical 1998, 133, 17-27) and sometimes require higher temperatures and pressures as is the case in U.S. Pat. No. 3,424,811.

Symmetrical dienes are reported in U.S. Pat. No. 3,878,262 with a yield value in the 80 to 90% range for 1,9-decadiene; however, the reaction was carried out at about 340° C. and 600 psi.
Recent advances in catalyst technology have not only improved yields but have reduced the reaction temperature to 30° C. and the pressure to 8 bar (116 psi) as disclosed in U.S. Pat. No. 5,342,985 which reported a 91% yield of 1,9-decadiene.

Many facilities do not have the capability of carrying out reactions under extreme conditions (even with the appropriate choice among the wide range of available catalysts, the support required heating at 550° C. for 2 hours prior to carrying out the metathesis reaction) or do not have the continuous feed equipment that is usually required for olefin metathesis to be successful. Facilities without the more specialized equipment would use a more traditional approach which includes, but is not necessarily limited to, dehydrohalogenation and Grignard chemistry.
Dehydrohalogenation is a time tested technique for the formation of an alkene. The technique generally works well in the laboratory and in production; however, there are potential problems associated with that type of chemistry including the possibility of passing over potentially offensive odors into a distilled product. The starting materials, which are in this case long chain α,ω-diols can be costly and the depicted process requires scrubbing to remove sulfur dioxide and hydrogen chloride. The actual elimination step requires the capability of being able to safely handle a strong moisture sensitive base like potassium t-butoxide in bulk.

The use of Grignard chemistry eliminates potential odor problems that may be associated with the above dehydrohalogenation chemistry and usually yields a product mixture with fewer impurities. In general, the raw materials are less costly and emissions are more easily dealt with. The chemistry is very well known and has been used for a few years more than one century (for a short review see Science of Synthesis 2004, 7, 573-596).
Grignard reagents are extremely valuable in chemical synthesis for the formation of carbon-carbon, carbon-phosphorus, carbon-silicon and other carbon-heteroatom bonds. Bonds of these types are formed with coupling reactions which fall into the class of a nucleophilic substitution reaction. A wide variety of substrates including carbon disulfide, carbon dioxide, aldehydes, ketones, esters, carboxylic acids (in particular formic acid where one equivalent of Grignard reagent is used to form the salt of the acid), acid halides, nitriles, epoxides, and a variety of phosphorous and silicon reagents have been used in such reactions with the only limitation being that the substrate cannot have an acidic hydrogen. The coupling reaction of an alkyl halide with a Grignard reagent has been known for more than 50 years and has some synthetic utility (see Kharasch and Reinmuth Grignard Reactions of Nonmetallic Substances; Prentice Hall: Englewood Cliffs, N.J., 1954 pp. 1046-1165). More recently Grignard reagents have been used by Knochel for the formation of polyfunctional aryl and heteroaryl magnesium reagents via a bromine magnesium exchange (see Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449-7453).
The copper catalyzed coupling reaction of a Grignard reagent with an organic halide, which is commonly referred to as a halide displacement reaction, was first reported in 1971 by Kochi and Tamura (J. Am. Chem. Soc. 1971, 93, 1487, Synthesis 1971, 303, J. Organomet. Chem. 1972, 42, 205). In the Synthesis paper the authors reported the coupling reaction of n-butylmagnesium bromide with n-hexyl bromide in the presence of dilithiumtetrachlorocuprate (Li2CuCl4). Since that report the use of Li2CuCl4 in coupling reactions has been quite extensive and is prominent in the synthesis of pheromones as well as in the synthesis of α,ω-olefins. One of the more interesting uses of this copper catalyzed coupling reaction may be found in U.S. Pat. No. 4,912,253 where sorbyl acetate was coupled with the Grignard prepared from the magnesium salt of chlorohexanol to form the codling moth (Laspeyresia pomonella) sex pheromone 8,10-dodecadien-1-ol on a metric ton scale. α,ω-olefins have been formed by coupling 4-pentenylmagnesium bromide with the bis-tosylate of 1,5-pentanediol to form 1,14-pentadecadiene in 81% yield (Tetrahedron 1991, 47, 6287-6292). 1,9-Decadiene has been prepared by the Li2CuCl4 catalyzed coupling reaction of 1,4-dibromobutane with allylmagnesium bromide at 25° C. in 38% yield (Synthetic Communications 1994, 24, 459-463).
U.S. Pat. No. 4,228,313 discloses a process for the coupling of a Grignard reagent with an allylic halide (typically a chloride) in an aprotic solvent (THF or ether) in the presence of a catalyst (CuCl, CuCl2, Li2CuCl4, FeCl3, and a variety of nickel and cobalt catalysts) for the purpose of improving the yield and increasing selectivity for the synthesis of a C15 compounds that make up a group of compounds related to vitamin E. In this invention the Grignard reagent was stirred with the catalyst at 35° C. for 1 hour followed by addition of this solution to the allylic chloride at the desired reaction temperature (typically 35° C.) or by adding the catalyst to the allylic halide and then carrying out the coupling reaction by the addition of the Grignard reagent to that solution at the desired reaction temperature. It should be noted that while there are some similarities of the invention outlined in U.S. Pat. No. 4,228,313 to the current invention there are differences with the primary one being the use of a bis-Grignard reagent for the exclusive formation of an α,ω-olefin. This example simply indicates how useful the copper catalyzed coupling reaction pioneered by Kochi and Tamura has been for chemistry in general.
The formation of a bis-Grignard reagent from an α,ω-dihalide is known in the literature; however, the use of such reagents does not appear to be wide spread. The Grignard reagent formed from 1,4-dibromobutane was first used in a coupling reaction with 2 equivalents of allyl bromide in 1911 as reported by Reformatskii et al (Berichte der Deutschen Chemischen Gesellschaft 1911, 44, 1885-1886) and then again by Braun, Deutsch, and Schnatloch in 1912 (Berichte der Deutschen Chemischen Gesellschaft 1912, 45, 1246-1263, 1,4-diiodobutane was used to prepare the bis-Grignard reagent). The preparation and use of 1,4-bis(chloromagnesium)butane was reported in U.S. Patent Application Publication No. 2003/0004357 and a similar example may be found in DE 4,411,101 (neither patent uses the bis-Grignard reagent in a halide displacement reaction). A more recent example of the coupling of a bis-Grignard reagent, for example, 1,5-bis(bromomagnesium)pentane, with a halide or organic ester such as an acetate (OAc) or an inorganic ester such as a p-toluenesulfonate (tosylate or OTs) in the presence of Li2CuCl3 or Li2CuCl4 was reported in Tetrahedron 1991, 47, 6287-6292 as shown below. However, this chemistry does not produce an olefinic product, but instead provides a potentially useful method for the preparation of long chain dichlorides which could themselves become candidates for conversion to long chain α,ω-olefins.

The present application describes a different and improved approach to the bulk synthesis of α,ω-olefins using this type of copper catalyzed coupling chemistry along with a significant improvement in the isolated yield over similar coupling reactions that use Grignard reagents.
The chemistry presented herein is of a type that does not require the use of extraordinary equipment (i.e. equipment that can handle higher pressure and temperature). However, the ability of the equipment to cryogenically cool the coupling reaction mixture is advantageous in order to maximize the yield and to improve the impurity profile (reduction of side reactions).